7

HIGHLIGHTS OF PRESCRIBING

INFORMATION

These highlights do not include all the

-----------WARNINGS AND PRECAUTIONS-------

information needed to use Bepreve™

(bepotastine besilate ophthalmic solution)

• To minimize the risk of contamination, do not
1.5% safely and effectively.
touch dropper tip to any surface. Keep bottle
See full prescribing information for
tightly closed when not in use. (5.1)
Bepreve™.
• Bepreve™ should not be used to treat contact
lens-related irritation. (5.2)
• Remove contact lenses prior to instillation of
BEPREVE™
Bepreve™. (5.2)
(bepotastine besilate ophthalmic solution) 1.5%
Initial U.S. Approval: 2009
-------------------ADVERSE REACTIONS-----------­
------------INDICATIONS AND USAGE--------- The most common adverse reaction occurring in
approximately 25% of patients was a mild taste
Bepreve™ is a histamine H1 receptor antagonist
following instillation. Other adverse reactions which
indicated for the treatment of itching associated
occurred in 2-5% of subjects were eye irritation,
with allergic conjunctivitis. (1)
headache, and nasopharyngitis. (6)

--------DOSAGE AND ADMINISTRATION---- To report SUSPECTED ADVERSE REACTIONS,

Instill one drop into the affected eye(s) twice a contact ISTA Pharmaceuticals, Inc. at 1-877-788-2020,
day. (BID). (2) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.

-------DOSAGE FORMS AND STRENGTHS-- See 17 for PATIENT COUNSELING

Solution containing bepotastine besilate, 1.5%. INFORMATION
(3) Revised: 08/2009

_____________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: 11 DESCRIPTION
CONTENTS* 12 CLINICAL PHARMACOLOGY
1 INDICATIONS AND USAGE 12.1 Mechanism of Action
2 DOSAGE AND ADMINISTRATION 12.3 Pharmacokinetics
3 DOSAGE FORMS AND STRENGTHS 13 NONCLINICAL TOXICOLOGY
4 CONTRAINDICATIONS 13.1 Carcinogenesis, Mutagenesis and Impairment
5 WARNINGS AND PRECAUTIONS of Fertility
5.1 Contamination of Tip and Solution 14 CLINICAL STUDIES
5.2 Contact Lens Use 16 HOW SUPPLIED/STORAGE AND
5.3 Topical Ophthalmic Use Only HANDLING
6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION
8 USE IN SPECIFIC POPULATIONS 17.1 Topical Ophthalmic Use Only
8.1 Pregnancy 17.2 Sterility of Dropper Tip
8.3 Nursing Mothers 17.3 Concomitant Use of Contact Lenses
8.4 Pediatric Use
8.5 Geriatric Use *Sections or subsections omitted from the full
prescribing information are not listed
____________________________________________________________________________________________

.
8
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Bepreve™ (bepotastine besilate ophthalmic
solution) 1.5% is a histamine H1 receptor
antagonist indicated for the treatment of itching
associated with signs and symptoms of allergic
conjunctivitis.
2 DOSAGE AND ADMINISTRATION
Instill one drop of Bepreve™ into the affected
eye(s) twice a day (BID).
3 DOSAGE FORMS AND STRENGTHS
Topical ophthalmic solution containing
bepotastine besilate 1.5%
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Contamination of Tip and Solution
To minimize contaminating the dropper tip and
solution, care should be taken not to touch the
eyelids or surrounding areas with the dropper tip
of the bottle. Keep bottle tightly closed when
not in use.
5.2 Contact Lens Use
Patients should be advised not to wear a contact
lens if their eye is red. Bepreve™ should not be
used to treat contact lens-related irritation.
Bepreve™ should not be instilled while wearing
contact lenses. Remove contact lenses prior to
instillation of Bepreve™. The preservative in
Bepreve™, benzalkonium chloride, may be
absorbed by soft contact lenses. Lenses may be
reinserted after 10 minutes following
administration of Bepreve™.
5.3 Topical Ophthalmic Use Only
Bepreve™ is for topical ophthalmic use only.
6 ADVERSE REACTIONS
The most common reported adverse reaction
occurring in approximately 25% of subjects was
a mild taste following instillation. Other adverse
reactions occurring in 2-5% of subjects were eye
irritation, headache, and nasopharyngitis.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: Teratogenicity studies
have been performed in animals. Bepotastine
besilate was not found to be teratogenic in rats
during organogenesis and fetal development at
oral doses up to 200 mg/kg/day (representing a
systemic concentration approximately 3300 times
that anticipated for topical ocular use in humans),
but did show some potential for causing skeletal
abnormalities at 1000 mg/kg/day. There were no
teratogenic effects seen in rabbits at oral does up
to 500 mg/kg/day given during organogenesis and
fetal development (>13,000 times the dose in
humans on a mg/kg basis). Evidence of infertility
was seen in rats given oral bepotastine besilate
1000 mg/kg/day, however, no evidence of
infertility was observed in rats given
200 mg/kg/day (approximately 3300 times the
topical ocular use in humans). The concentration
of radiolabeled bepotastine besilate was similar in
fetal liver and maternal blood plasma following a
single 3 mg/kg oral dose. The concentration in
other fetal tissues was one-third to one-tenth the
concentration in maternal blood plasma.
An increase in stillborns and decreased growth
and development were observed in pups born from
rats given oral doses of 1000 mg/kg/day during
perinatal and lactation periods. There were no
observed effects in rats treated with 100
mg/kg/day.
There are no adequate and well-controlled studies
of bepotastine besilate in pregnant women.
Because animal reproduction studies are not
always predictive of human response, Bepreve™
(bepotastine besilate ophthalmic solution) 1.5%
should be used during pregnancy only if the
potential benefit justifies the potential risk to the
fetus.
8.3 Nursing Mothers
Following a single 3 mg/kg oral dose of radio-
labeled bepotastine besilate to nursing rats 11
days after delivery, the maximum concentration
of radioactivity in milk was 0.40 µg eq/mL 1
hour after administration; at 48 hours after
administration the concentration was below
detection limits. The milk concentration was
higher than the maternal blood plasma
concentration at each time of measurement.
It is not known if bepotastine besilate is excreted
in human milk. Caution should be exercised
when Bepreve™ (bepotastine besilate
ophthalmic solution) 1.5% is administered to a
nursing woman.
8.4 Pediatric Use
Safety and efficacy of Bepreve (bepotastine
besilate ophthalmic solution) 1.5% have not
9
been established in pediatric patients under 2
years of age. Efficacy in pediatric patients
under 10 years of age was extrapolated from
clinical trials conducted in pediatric patients
greater than 10 years of age and from adults.
8.5 Geriatric Use
No overall difference in safety or effectiveness
has been observed between elderly and
younger patients.
11 DESCRIPTION
Bepreve™ (bepotastine besilate ophthalmic
solution) 1.5% is a sterile, topically
administered drug for ophthalmic use. Each
mL of Bepreve™ contains 15 mg bepotastine
besilate. Bepotastine besilate is designated
chemically as (+) -4-[[(S)-p-chloro-alpha -2­
pyridylbenzyl]oxy]-1-piperidine butyric acid
monobenzenesulfonate. The chemical
structure for bepotastine besilate is:
Bepotastine besilate is a white or pale
yellowish crystalline powder. The molecular
weight of bepotastine besilate is 547.06
daltons. Bepreve™ ophthalmic solution is
supplied as a sterile, aqueous 1.5% solution,
with a pH of 6.8.
The osmolality of Bepreve™ (bepotastine
besilate ophthalmic solution) 1.5% is
approximately 290 mOsm/kg.
Each mL of Bepreve™ (bepotastine besilate
ophthalmic solution) 1.5% contains:
Active:
Bepotastine besilate15 mg (equivalent to 10.7
mg bepotastine)
Preservative: benzalkonium chloride 0.005%
Inactives: monobasic sodium phosphate
dihydrate, sodium chloride, sodium hydroxide
to adjust pH, and water for injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bepotastine is a topically active, direct H1­
receptor antagonist and an inhibitor of the
release of histamine from mast cells.
12.3 Pharmacokinetics
Absorption: The extent of systemic exposure
to bepotastine following topical ophthalmic
administration of bepotastine besilate 1% and
1.5% ophthalmic solutions was evaluated in 12
healthy adults. Following one drop of 1% or
1.5% bepotastine besilate ophthalmic solution
to both eyes four time daily (QID) for seven
days, bepotastine plasma concentrations
peaked at approximately one to two hours
post-instillation. Maximum plasma
concentration for the 1% and 1.5% strengths
were 5.1 ± 2.5 ng/mL and 7.3 ± 1.9 ng/mL,
respectively. Plasma concentration at 24 hours
post-instillation were the below quantifiable
limit (2ng/mL) in 11/12 subjects in the two
dose groups.
Distribution: The extent of protein binding of
bepotastine is approximately 55% and
independent of bepotastine concentration.
Metabolism: In vitro metabolism studies with
human liver microsomes demonstrated that
bepotastine is minimally metabolized by
CYP450 isozymes.
In vitro studies demonstrated that bepotastine
besilate does not inhibit the metabolism of
various cytochrome P450 substrate via
inhibition of CYP3A4, CYP2C9, and
CYP2C19. The effect of bepotastine besilate
on the metabolism of substrates of CYP1A2,
CYP2C8, CYP2D6 was not studied.
Bepotastine besilate has a low potential for
drug interaction via inhibition of CYP3A4,
CYP2C9, and CYP2C19.
Excretion: The main route of elimination of
bepotastine besilate is urinary excretion (with
approximately 75-90% excreted unchanged in
urine).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis and
Impairment of Fertility
Long term dietary studies in mice and rats were
conducted to evaluate the carcinogenic
potential of bepotastine besilate. Bepotastine
besilate did not significantly induce neoplasms
in mice receiving a nominal dose of up to
200 mg/kg/day for 21 months or rats receiving
a nominal dose of up to 97 mg/kg/day for 24
months. Theses dose levels represent systemic
exposures approximating 350 and 200 times
that achieved with human topical ocular use.
The no observable adverse effect level for
10

bepotastine besilate based on nominal dose 17.2 Sterility of Dropper Tip

levels in carcinogenicity tests were 18.7 to 19.9
mg/kg/day in mice and 9.6 to 9.8 mg/kg/day in
rats (representing exposure margins of
approximately 60 and 20 times the systemic
exposure anticipated for human topical use).
There was no evidence of genotoxicity in the
Ames test, in CHO cells (chromosome
aberrations), in mouse hepatocytes
(unscheduled DNA synthesis), or in the mouse
micronucleus test.
When oral bepotastine was administered to
male and female rats at doses up to 1,000
mg/kg/day, there was a slight reduction in
fertility index and surviving fetuses. Infertility
was not seen in rats given 200 mg/kg/day oral
bepotastine besilate (approximately 3300 times
the systemic concentration anticipated for
Patients should be advised to not touch dropper
tip to any surface, as this may contaminate the
contents.
17.3 Concomitant Use of Contact Lenses
Patients should be advised not to wear a
contact lens if their eye is red. Patients should
be advised that Bepreve™ should not be used
to treat contact lens-related irritation.
Patients should also be advised to remove
contact lenses prior to instillation of
Bepreve™. The preservative in Bepreve™,
benzalkonium chloride, may be absorbed by
soft contact lenses. Lenses may be reinserted
after 10 minutes following administration of
Bepreve™.
©ISTA Pharmaceuticals, Inc.
Manufactured for: ISTA Pharmaceuticals®,

topical ocular use in humans). Inc.

Irvine, CA 92618

14 CLINICAL STUDIES
Clinical efficacy was evaluated in 2 By: Bausch & Lomb Incorporated

conjunctival allergen challenge (CAC) studies Tampa, FL 33637

(237 patients). Bepreve (bepotastine besilate

ophthalmic solution) 1.5% was more effective Under license from:

than its vehicle for relieving ocular itching Senju Pharmaceutical Co., Ltd.

induced by an ocular allergen challenge, both Osaka, Japan 541-004

at CAC 15 minutes post-dosing and a CAC 8

®
hours post dosing of Bepreve. and ™ marks owned by ISTA
Pharmaceuticals, Inc.
The safety of Bepreve™ was evaluated in a U.S. Patents: 6,307,052; 6,780,877
randomized clinical study of 861 subjects over
a period of 6 weeks.

16 HOW SUPPLIED/STORAGE AND

HANDLING
Bepreve™ (bepotastine besilate ophthalmic
solution) 1.5% is supplied in a white low
density polyethylene plastic squeeze bottle
with a white controlled dropper tip and a white
polypropylene cap in the following sizes:

2.5 mL (NDC 67425-007-12)

5 mL (NDC 67425-007-50)

10 mL (NDC 67425-007-75)

STORAGE
Store at 15º – 25ºC (59º – 77ºF).

17 PATIENT COUNSELING INFORMATION

17.1 Topical Ophthalmic Use Only
For topical ophthalmic administration only.